Throughout this application, various references are referred to within parentheses. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
The designation xe2x80x9cxcex11Axe2x80x9d is the appellation recently approved by the IUPHAR Nomenclature Committee for the previously designated xe2x80x9cxcex11Cxe2x80x9d cloned subtype as outlined in the 1995 Receptor and Ion Channel Nomenclature Supplement (Watson and Girdlestone, 1995). The designation xcex11A is used throughout this application and the supporting tables and figures to refer to this receptor subtype. At the same time, the receptor formerly designated xcex11A was renamed xcex11D. The new nomenclature is used throughout this application. Stable cell lines expressing these receptors are described herein; however, these cell lines were deposited with the American Type Culture Collection (ATCC) under the old nomenclature (infra).
Benign Prostatic Hyperplasia (BPH), also called Benign Prostatic Hypertrophy, is a progressive condition which is characterized by a nodular enlargement of prostatic tissue resulting in obstruction of the urethra. This results in increased frequency of urination, nocturia, a poor urine stream and hesitancy or delay in starting the urine flow. Chronic consequences of BPH can include hypertrophy of bladder smooth muscle, a decompensated bladder and an increased incidence of urinary tract infection. The specific biochemical, histological and pharmacological properties of the prostate adenoma leading to the bladder outlet obstruction are not yet known. However, the development of BPH is considered to be an inescapable phenomenon for the aging male population. BPH is observed in approximately 70% of males over the age of 70. Currently, in the United States, the method of choice for treating BPH is surgery (Lepor, H., Urol. Clinics North Amer., 17, 651 (1990)). Over 400,000 prostatectomies are performed annually (data from 1986).
Transurethral resection of the prostate (TURP) was used in approximately 180,000 men in the United States in 1996. This surgical procedure results in significant benefit. However, because of its potential adverse consequences, surgery is an unattractive alternative for many patients and is not recommended for elderly patients due to the potential for complications. Another surgical procedure, transurethral needle ablation (TUNA), was recently approved by the FDA and may have the advantage of possible use on an out-patient basis under local anesthesia. However, initial results of a recent study comparing TURP and TUNA show a lower level of efficacy in TUNA than in TURP with respect to increasing urinary flow.
A medicinal alternative to surgery is clearly very desirable. The limitations of surgery for treating BPH include the morbidity rate of an operative procedure in elderly men, persistence or recurrence of obstructive and irritative symptoms, as well as the significant cost of surgery. xcex1-Adrenergic receptors (McGrath, et. al. Med. Res. Rev., 9, 407-533, 1989) are specific neuroreceptor proteins located in the peripheral and central nervous systems on tissues and organs throughout the body. These receptors are important switches for controlling many physiological functions and, thus, represent important targets for drug development. In fact, many xcex1-adrenergic drugs have been developed over the past 40 years. Examples include clonidine, phenoxybenzamine and prazosin (treatment of hypertension), naphazoline (nasal decongestant), and apraclonidine (treating glaucoma). xcex1-Adrenergic drugs can be broken down into two distinct classes: agonists (clonidine and naphazoline are agonists), which mimic the receptor activation properties of the endogenous neurotransmitter norepinephrine, and antagonists (phenoxybenzamine and prazosin are antagonists), which act to block the effects of norepinephrine. Many of these drugs are effective but also produce unwanted side effects (for example, clonidine produces dry mouth and sedation in addition to its antihypertensive effects).
During the past 15 years a more precise understanding of xcex1-adrenergic receptors and their drugs has evolved through increased scientific scrutiny. Prior to 1977, only one xcex1-adrenergic receptor was known to exist. Between 1977 and 1988, it was accepted by the scientific community that at least two xcex1-adrenergic receptorsxe2x80x94xcex11 and xcex12xe2x80x94existed in the central and peripheral nervous systems. Since 1988, new techniques in molecular biology have led to the identification of at least six xcex1-adrenergic receptors which exist throughout the central and peripheral nervous systems: xcex11A (new nomenclature), xcex11B, xcex11D (new nomenclature), xcex12A, xcex12B and xcex12C (Bylund, D. B., FASEB J., 6, 832 (1992)). In many cases, it is not known precisely which physiological responses in the body are controlled by each of these receptors. In addition, current xcex1-adrenergic drugs are not selective for any particular xcex1-adrenergic receptor. Many of these drugs produce untoward side effects which may be attributed to their poor xcex1-adrenergic receptor selectivity.
Since the mid 1970""s, nonselective xcex1-antagonists have been prescribed to treat BPH. In 1976, M. Caine, et al. (Brit. J. Urol., 48, 255 (1976)), reported that the nonselective xcex1-antagonist phenoxybenzamine was useful in relieving the symptoms of BPH. This drug may produce its effects by interacting with xcex1-receptors located on the prostate. However, this drug also produces significant side effects such as dizziness and asthenia which severely limit its use in treating patients on a chronic basis. More recently, the xcex1-adrenergic antagonists prazosin and terazosin have also been found to be useful for treating BPH. However, these drugs also produce untoward side effects. It has recently been discovered that the xcex11A receptor is responsible for mediating the contraction of human prostate smooth muscle (Gluchowski, C. et. al., WO 94/10989, 1994; Forray, C. et. al., Mol. Pharmacol. 45, 703, 1994). This discovery indicates that the xcex11A antagonists may be effective agents for the treatment of BPH with decreased side effects. Further studies have indicated that the xcex11A receptor may also be present in other lower urinary tract tissues, such as urethral smooth muscle (Ford et al. Br. J. Pharmacol., 114, 24P, (1995)).
This invention is directed to oxazolidinone compounds which are selective antagonists for cloned human xcex11A receptors. This invention is also related to uses of these compounds for lowering intraocular pressure (Zhan, et. al. Ophthalmol. Vis. Sci., 34 Abst. #1133, 928, 1993), inhibiting cholesterol synthesis (D""Eletto and Javitt, J. Cardiovascular Pharmacol., 13 (Suppl. 2) S1-S4, 1989), benign prostatic hyperplasia, impotency (Milne and Wyllie, EP 0 459 666 A2, 1991), sympathetically mediated pain (Campbell, WO 92/14453, 1992), cardiac arrhythmia (Spiers, et. al., J. Cardiovascular Pharmacol., 16, 824-830, 1990) and for the treatment of any disease where antagonism of the xcex11A receptor may be useful.
This invention is directed to a compound having the structure: 
wherein each X is independently O or S;
wherein q is 1 or 2;
wherein each R2 is independently H; xe2x80x94(CH2)tXR3; xe2x80x94(CH2)tC(X)NR3; xe2x80x94(CH2)tCO2R3; xe2x80x94CO2R3; straight chained or branched C1-C7 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each t is an integer from 1 to 4 inclusive;
wherein each R3 is independently H; straight chained or branched C1-C7 alkyl, straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein R4 is aryl, heteroaryl, C1-C7 alkyl substituted with one or two aryl, or C1-C7 alkyl substituted with one or two heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R3)2, xe2x80x94COR3, xe2x80x94(CH2)tXR3, xe2x80x94(CH2)nC(X)NR3, xe2x80x94(CH2)nCO2R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C2-C7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each n independently is an integer from 0 to 7 inclusive;
wherein R5 is H; aryl, C1-C7 alkyl substituted with aryl, heteroaryl, or C1-C7 alkyl substituted with heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R3)2, xe2x80x94COR3, xe2x80x94(CH2)tXR3, xe2x80x94(CH2)nC(X)NR3, xe2x80x94(CH2)nCO2R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C2-C7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
where R5 and one R2 on adjacent carbon atoms together may form aryl, heteroaryl, indane or tetrahydronaphthyl, C3-C7 cycloalkyl, or heterocycloalkyl wherein one or two heteroatoms may be O, N or S;
wherein R1 is 
where each R6 is independently H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, xe2x80x94(CH2)nXR3, xe2x80x94COR3, xe2x80x94(CH2)nC(X)N(R3)2, xe2x80x94(CH2)nCO2R3, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R3)2, xe2x80x94SO2R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl;
where each R7 is independently H; F; Cl; Br; I; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94(CH2)nXR3; xe2x80x94COR3; xe2x80x94(CH2)nC(X)N(R3)2; xe2x80x94(CH2)nCO2R3; xe2x80x94CN; xe2x80x94NO2; xe2x80x94N(R3)2; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl, wherein the alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, xe2x80x94(CH2) XR3, xe2x80x94COR3, xe2x80x94(CH2)nC(X)N(R3)2, xe2x80x94(CH2)nCO2R3, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R3)2, xe2x80x94SO2R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyf luoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, xe2x80x94(CH2)nXR3, xe2x80x94COR3, xe2x80x94(CH2)nC(X)N(R3)2, xe2x80x94(CH2)nCO2R3, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R3)2, xe2x80x94SO2R3, straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl or polyflouroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl;
wherein each R10 is independently H; (CH2)tXR3; (CH2)tC(X)NR3; (CH2)tCO2R3; straight chained or branched C1-C7 alkyl or carboxamidoalkyl; straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein R11 is aryl, heteroaryl, C1-C7 alkyl substituted with one or two aryl, or C1-C7 alkyl substituted with one or two heteroaryl; wherein any aryl or heteroaryl independently may be substituted with one or more of F, Cl, Br, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R3)2, xe2x80x94COR3, xe2x80x94(CH2)nXR3, xe2x80x94(CH2)nC(X)NR3, xe2x80x94(CH2)nCO2R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or carboxamidoalkyl, straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each m independently is an integer from 0 to 3 inclusive;
wherein Z is 
xe2x80x83or C2-C7 alkenyl, wherein the C2-C7 alkenyl may be unsubstituted or substituted with one or more R9 groups;
where R8 is H; (CH2)tXR3; (CH2)tC(X)NR3; (CH2)tCO2R3; straight chained or branched C1-C7 alkyl, carboxamidoalkyl; straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
where each R9 is independently H; F; Cl; Br; I; (CH2)mXR3; (CH2)mC(X)NR3; (CH2)mCO2R3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein Y is S, O, or NR8;
or a pharmaceutically acceptable salt thereof.
The present invention is additionally directed to a compound having the structure: 
This invention is additionally directed to a compound having the structure: 
wherein each W is an integer from 0 to 3 inclusive;
wherein each W1 is an integer from 0 to 3 inclusive;
wherein each X is independently O or S;
wherein X1 is O, S, NR3;
wherein each R2 is independently H; xe2x80x94(CH2)tXR3; xe2x80x94(CH2)tC(X)NR3; xe2x80x94(CH2)tCO2R3; xe2x80x94CO2R3; straight chained or branched C1-C7 alkyl, aminoalkyl, carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each t is an integer from 1 to 4 inclusive;
wherein each R3 is independently H; straight chained or branched C1-C7 alkyl, straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein R4 is aryl, heteroaryl, C1-C7 alkyl substituted with one or two aryl, or C1-C7 alkyl substituted with one or two heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R3)2, xe2x80x94COR3, xe2x80x94(CH2)tXR3, xe2x80x94(CH2)nC(X)NR3, xe2x80x94(CH2)nCO2R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C2-C7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each n independently is an integer from 0 to 7 inclusive;
wherein R5 is H; aryl, C1-C7 alkyl substituted with aryl, heteroaryl, or C1-C7 alkyl substituted with heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R3)2, xe2x80x94COR3, xe2x80x94(CH2)tXR3, xe2x80x94(CH2)nC(X)NR3, xe2x80x94(CH2)nCO2R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C2-C7 aminoalkyl, alkenyl or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein R1 is 
where each R6 is independently H; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, monoflouroalkyl or polyflouroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, xe2x80x94(CH2)nXR3, xe2x80x94COR3, xe2x80x94(CH2)nC(X)N(R3)2, xe2x80x94(CH2)nCO2R3, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R3)2, xe2x80x94SO2R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl;
where each R7 is independently H; F; Cl; Br; I; xe2x80x94COR3; xe2x80x94CO2R3; xe2x80x94(CH2)nXR3; (CH2)nC(X)N(R3)2; xe2x80x94(CH2)nCO2R3; xe2x80x94CN; xe2x80x94NO2; xe2x80x94N(R3)2; straight chained or branched C1-C7 alkyl, hydroxyalkyl, aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl, wherein the alkyl, aminoalkyl, carboxamidoalkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl may be substituted with one or more aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, xe2x80x94(CH2)nXR3, xe2x80x94COR3, xe2x80x94(CH2)nC(X)N(R3)2, xe2x80x94(CH2)nCO2R3, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R3)2, xe2x80x94SO2R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl; aryl or heteroaryl, wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, xe2x80x94(CH2)nXR3, xe2x80x94COR3, xe2x80x94(CH2)nC(X)N(R3)2, xe2x80x94(CH2)nCO2R3, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R3)2, xe2x80x94SO2R3, straight chained or branched C1-C7 alkyl, straight chained or branched C1-C7 monofluoroalkyl or polyfluoroalkyl, straight chained or branched C2-C7 alkenyl or alkynyl, or C3-C7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C5-C7 cycloalkenyl;
wherein each R10 is independently H; (CH2)tXR3;
(CH2)tC(X)NR3; (CH2)tCO2R3; straight chained or branched C1-C7 alkyl or carboxamidoalkyl; straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein R11 is aryl, heteroaryl, C1-C7 alkyl substituted with one or two aryl, or C1-C7 alkyl substituted with one or two heteroaryl; wherein any aryl or heteroaryl independently may be substituted with one or more of F. Cl, Br, I, xe2x80x94CN, xe2x80x94NO2, xe2x80x94N(R3)2, xe2x80x94COR3, xe2x80x94(CH2)nXR3, xe2x80x94(CH2)nC(X)NR3, xe2x80x94(CH2)nCO2R3, straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, or carboxamidoalkyl, straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl, or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein each m independently is an integer from 0 to 3 inclusive;
wherein Z is 
xe2x80x83or C2-C7 alkenyl, wherein the C2-C7 alkenyl may be unsubstituted or substituted with one or more R9 groups;
where R8 is H; (CH2)tXR3; (CH2)tC(X)NR3; (CH2)tCO2R3; straight chained or branched C1-C7 alkyl, carboxamidoalkyl; straight chained or branched C2-C7 aminoalkyl, alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
where each R9 is independently H; F; Cl; Br; I; (CH2)mXR3; (CH2)mC(X)NR3; (CH2)mCO2R3; straight chained or branched C1-C7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C2-C7 alkenyl, or alkynyl; or C3-C7 cycloalkyl or C5-C7 cycloalkenyl;
wherein Y is S, O, or NR8;
or a pharmaceutically acceptable salt thereof.
This invention is also related to uses of these compounds for lowering intraocular pressure, inhibiting cholesterol synthesis, relaxing lower urinary tract tissue, the treatment of benign prostatic hyperplasia, impotency, cardiac arrhythmia and for the treatment of any disease where antagonism of the xcex11A receptor may be useful. The invention further provides pharmaceutical compositions comprising a therapeutically effective amount of the above-defined compounds and a pharmaceutically acceptable carrier.